Variant 4-163854046-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001394959.1(MARCHF1):c.86C>A(p.Ala29Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,536,706 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000098 ( 2 hom. )

Consequence

MARCHF1
NM_001394959.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.20

Variant links:

Genes affected

MARCHF1 (HGNC:26077): (membrane associated ring-CH-type finger 1) MARCH1 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases (EC 6.3.2.19). MARCH proteins add ubiquitin (see MIM 191339) to target lysines in substrate proteins, thereby signaling their vesicular transport between membrane compartments. MARCH1 downregulates the surface expression of major histocompatibility complex (MHC) class II molecules (see MIM 142880) and other glycoproteins by directing them to the late endosomal/lysosomal compartment (Bartee et al., 2004 [PubMed 14722266]; Thibodeau et al., 2008 [PubMed 18389477]; De Gassart et al., 2008 [PubMed 18305173]).[supplied by OMIM, Mar 2010]

MARCHF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04449776).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARCHF1	NM_001394959.1 linkuse as main transcript	c.86C>A	p.Ala29Asp	missense_variant	4/10	ENST00000514618.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARCHF1	ENST00000514618.6 linkuse as main transcript	c.86C>A	p.Ala29Asp	missense_variant	4/10	5	NM_001394959.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000173

AC:

AN:

144518

Hom.:

AF XY:

0.000208

AC XY:

AN XY:

77106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000814

Gnomad ASJ exome

AF:

0.000119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000528

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000975

AC:

135

AN:

1384538

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

683192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000140

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000568

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000658

Gnomad4 OTH exome

AF:

0.000207

GnomAD4 genome

AF:

0.000125

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000174

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.86C>A (p.A29D) alteration is located in exon 3 (coding exon 1) of the MARCH1 gene. This alteration results from a C to A substitution at nucleotide position 86, causing the alanine (A) at amino acid position 29 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.031

T;T;.;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.66

T;.;T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.044

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.42

N;N;N;N

REVEL

Benign

0.059

Sift

Uncertain

0.018

D;D;D;D

Sift4G

Benign

0.43

T;T;D;T

Polyphen

0.0080

B;B;.;.

Vest4

0.25

MutPred

0.28

Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);

MVP

0.43

MPC

0.58

ClinPred

0.042

GERP RS

4.5

Varity_R

0.16

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over